Abstract

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

A histogram with 20 bins of 9870 correlation values among 141 analytes over all 107 subjects.

The shown distribution is a Johnson SU fit with four parameters: gamma = −1.2967, delta = 2.2624, lambda = 0.26593, xi = −0.12371. The present study is distinguished from many others by focusing on the tail of very strong, positive correlations (blue box) that are not balanced by any negative correlations of the same magnitude

Blood plasma proteins are labeled by their gene common symbols. The correlations in orange appear in all three graphs. We note eight analytes that include SERPINE1, and in particular SERPINE1 correlations include the matrix metalloproteinases MMP7, MMP9, and MMP10. MMP9t denotes an assay for both pro-MMP9 and mature MMP9

Four SERPINE1 correlations are present, suggesting changes in requlation of the SERPINE1 gene compared to unaffected and nonconverter assays. Remarkable is the gained correlation of SERPINE1 and TIMP1 because both proteins inhibit anticogulation and vascular remodeling in some contexts and both generally promote anti-inflammation. Furthermore, TIMP1 is completely absent in unaffected and nonconverter graphs. Also, the strong SERPINE1 correlations with matrix metalloproteinases (MMPs) in the unaffected graph are absent in this converter graph